New chromatin analysis technique predicts cell behavior

Genetic and epigenetic analysis techniques are essential tools for understanding what goes on inside the cells and tissues of our bodies: in fact, the development of new therapeutic strategies and the study of their effectiveness depends on these very techniques.

Thanks to the work of a group of researchers at the Center for Omics Science, headed by Giovanni Tonon, scientists now have a new and powerful tool at their disposal. It is called “scGET-seq” and it was developed under the coordination of Francesca Giannese and Davide Cittaro, heads of the bioinformatics area of the recently opened Innovation Lab, and Giovanni Tonon himself.

The tool, described on Nature Biotechnology, will make possible to obtain simultaneously – and for each individual cell in a tissue – both the DNA sequence and its state of compaction in the nucleus, which provides valuable information for predicting the cell's behavior. Thanks to this new technique, scientists will be able to better study highly dynamic cell systems such as embryonic development, regenerative medicine and cancer.


Chromatin and cell behavior

DNA is stored in the cell nucleus in a highly compact form: it is wound up several times around specific proteins, like a dense ball of yarn. It is only thanks to this conformation that DNA – which is about 2 meters long and rather fragile – is able to remain stable inside cells.

The assembly of DNA and the proteins around which it is compacted is called chromatin and it is a highly dynamic structure. The cell constantly needs access to different parts of the DNA sequence to read the genes and translate them into proteins, which means that chromatin must constantly open and close at different points.

“If knowing the DNA sequence of a cell gives us a lot of information about its identity - because it tells us what, potentially, is capable of doing - the state of opening and closing of chromatin tells us more about how the cell is behaving,” explains Francesca Giannese. “Chromatin opening is in fact necessary to gain access to a given portion of DNA and thus to translate a gene into a protein and activate any cellular process. Our technique allows us to obtain both pieces of information.”


Predicting cell behavior

Researchers at Centre for Omics Science developed this new technique from an enzyme that already exists in nature, whose usual task is to move pieces of the genome from one position in the sequence to another, through a cut-and-fix process. By engineering the enzyme, the researchers succeeded in obtaining a completely new biotechnological tool: a molecule capable of reading the open state of chromatin and the DNA sequence at the same time.

“The level of information obtained for each individual cell is detailed enough to allow us - using a computational approach - to build a predictive model of cell behavior,” Davide Cittaro continues. “We are able to understand, starting from the chromatin conformation, in which direction the cells of a tissue are going: which genes are activating and therefore which cellular programs they are starting”.

This can have a very important implication in the study of highly dynamic systems, such as cancer. Cancer cells are indeed under considerable selective pressure and are therefore constantly changing.

“The evolution of cancer cells towards increasingly aggressive behavior and the development of drug resistance phenomena are only partly due to the emergence of new mutations in the tumor DNA,” explains Giovanni Tonon. “An important part of these new tumor abilities depends instead on changes in the cell's behavior, i.e. epigenetic modifications: what changes is the way tumor cells read and use DNA, not the DNA itself. This is why the tool we have developed is so important for cancer research: it will help us to predict and better understand the behavior of diseased cells, helping us to develop new therapies and more precise approaches.”

The research was made possible thanks to support from the AIRC Foundation for Cancer Research, Cancer Research UK and the Italian Ministry of Health.